CYP3A activity should not be viewed as a single enzyme or a linear pathway; rather it is influenced by sequence diversity in CYPSAs, drug transporters and TFs (Figure 1). This extends the progress made in the first years of this grant (p. 211) to discover the additional sequence variations contributing to CYP3A phenotypic diversity. We extensively resequenced CYP3A4 and CYPSAS coding regions (Figure 18) and found that coding SNPs do not explain human variation in CYP3A4 expression or activity, nor do they explain the variable expression of CYPSAS in CYP3A5*! carriers (expressors) (248). Therefore, we hypothesize that sequence variation in the CYP3A non-coding regions (cis-acting loci) and interindividual differences in the expression of hepatic-enriched TFs and transporters are responsible for variation in constitutive and inducible CYP3A expression. Indeed, such a notion is entirely consistent with the growing body of evidence that both cis- and trans-acting loci regulate variation in human gene expression (150). We will follow the PAAR general approach (p. 242) to identify and prioritize candidate TFs whose expression is associated with constitutive and inducible CYP3A expression in human liver (Step 1), identify and prioritize candidate polymorphisms in TFs associated with CYP3A expression (Step 2), and conduct association studies of candidate polymorphisms (Step 3).